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The Human Genome Project 2000

The end of the beginning NS 20-8-00

The first draft of the human genome signals a new era for humanity

'A few months ago, I compared the project to the invention of the wheel. On reflection, it's more than that ... this code is the essence of mankind' Mike Dexter, Welcome MW

IT TOOK more than a decade of effort, but Monday 26 June 2000 will be remembered as the day when humankind learned, in a sense, what it is to be human. Heads of government and Nobel laureates came together to hail the arrival of a "working draft" of the human genome: the set of genetic instructions which governs the assembly and function of all human beings. There may still be some holes to fill in, and the raw genetic information presented this week may take decades to decipher fully, but for researchers across the globe Monday was a day for celebration. "This is the most wondrous map ever produced by mankind," Bill Clinton told a press conference at the White House. In another, video-linked press conference in London, Tony Blair called the sequencing of the human genome "a breakthrough that opens the way for massive advancement in the treatment of cancer and hereditary diseases, and that is only the beginning". The scale of this triumph of biological science is awesome. The 24 different human chromosomes may be too small for the eye to see, but each set contains 3:1 billion base pairs: a code written in 3.1 billion "letters". This amount of data is equivalent to the contents of 200 telephone directories, each 500 pages long. Reading that code took the combined efforts of thousands of researchers, and countless hours of work by hundreds of state-of-the-art robotic sequencing machines humming quietly around the clock in pristine laboratories. Each machine prepares DNA samples, runs them through electrophoresis gels, and reads off the results into a database, only requiring the help of a human once every 24 hours. In deciphering the human genome, biology became a truly industrial process. But staggering statistics and engineering feats were not the only things drawing attention to the human genome effort in recent months. This was amply demonstrated by the fact that Francis Collins, director of the National Human Genome Research Institute near Washington DC and head of the Human Genome Project, was not the only person standing next to Clinton on Monday. At the President's other shoulder was Craig Venter, the maverick gene entrepreneur who two years ago formed the sequencing company Celera Genomics and set out to be the first to sequence the human genome. Before Venter's dramatic intervention, the $300 million, publicly funded sequencing effort, which began in 1990, had set itself a completion date of 2005. Venter upped the stakes by saying that Celera, based in Rockville, Maryland, would sequence the lot by 2001 using a wholegenome "shotgun" sequencing technique (New Scientist, 23 May 1998, p 4). Fearing that Venter would keep the data secret and attempt to monopolise it by patenting genes, the publicly funded researchers redoubled their efforts and maintained their policy of putting sequence data onto the Web the moment it was obtained, with free access to all. As a result, the human genome effort became a race. Last autumn, with completion within sight, the two groups held talks about collaborating and merging data, but this dialogue broke down amid bitter public accusations from both sides. In the spring, however, there was another attempt at reconciliation. Collins says that in late April he called Ari Petrinos, head of the US Department of Energy's human genome programme, and asked him to try to broker a meeting with Venter. Petrinos invited the two geneticists over to his house on the night of 7 May for beer and pizza. That first secret meeting quickly led to three more, the last of which was held a week ago. Collins jokes, "Craig's wife is beginning to suspect that something is going on because we're spending so much time together in the evening." But this time the deal on the table was merely for the groups to make a simultaneous announcement and submit separate papers for simultaneous publication. "There are several scientific journals that have been wooing us," says Venter. Speaking on Monday, Venter and Collins even played down the idea that a race to sequence the genome had taken place. "We felt it was important for us to rise above the squabbles that you've read about," said Venter. Collins agreed: 'It seemed absolutely the right moment to sit down together." Others in the public team were more candid about the effect of Venter's efforts. John Sulston, director of the Sanger Centre near Cambridge, which provided one-third of the sequence data, said at a press conference in London: "I don't want my genetic information to be under the control of any one enfity or corporation. We had to fight, I regret that, and it hasn't been easy." Sulston adds, however, that the competition "sharpened people's desire to produce something". But he says, "it only accelerated it by a year".

'Not very many years from now, people will be sequencing individual humans, every organism on the planet'

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After publication later this year, the two groups will hold a meeting to review the data generated by the different sequencing approaches adopted by the two teams-information that may aid efforts to sequence other genomes. That meeting is going to be "incredibly interesting and a lot of fun", says Collins. He describes the two approaches as "different but complementary". Each approach will serve to validate the other. The research groups were excited, for examplei by the fact that they came up with strikingly similar figures for the total number of base pairs in the genome. The public project estimates that the human genome comprises 3.15 bilhon base pairs or "letters", while Celera's assembled genome has 3.12 bilhon. 'Our numbers are so close," says Eric Lander, director of the Whitehead Institute Center for Genome Research in Boston, who claims the two groups didn't even check their figures against each other until the mon-dng of the announcement. Those numbers will remain estimates for some time to come as stubbom gaps remain in the genome. Jane Rogers, project manager of human sequencing at the Sanger Centre, says that 97 per cent of the gene-bearing regions of the genome have now been posted on the Internet as overlapping clones. However, 12 per cent of that remains unsequenced, and only 24 per cent has been checked as being fully accurate. "We'd always said when the rough draft was ready, it would be released," says Mike Dexter, director of the Wellcome Trust, the London-based charity which pumped $120 million into the public project. "Also, there's been intense media interest and it was right to put it out-the timing was fine," he says. What makes the publicly funded working draft "ready" is the fact that the gene fragments overlap to form a rugged gene map reaching from tip to tip of every chromosome. "It's allowed us a view over the whole genome, from end to end," Rogers says. The next job is to continue sequencing and fill in the gaps to complete what will become a 'gold standard" reference genome by 2003. Interpreting this vast store of raw genetic data remains a huge task, however. Collins says that in the past six months, scientists have identified a dozen different disease-related genes using the public database on the Internet. The current total of known genes is 38 000.

'We share half our genes with the banana'

While some estimates for the final total put the figure at well over 100 000, Lander says the "best guesses are more in the 50 000 to 60 000 range". A group of 200 genome researchers have set up a betting pool on the intemet to guess the final number. 'AU of those in the betting pool under 38 000 have to give up their $1 bet," says Collins, who has his money on 48 011. Other genomes, vital for working out the function of the newly sequenced human genes, are now in the works. Celera plans to have the mouse genome sequenced by the end of the year. The public genome project is working on the genomes of another strain of mouse, the rat and the zebrafish. "Not very many years from now, people will be sequencing individual humans, every organism on the planet," says Lander. Andy Coghlan and Nell Boyce

'lt seemed absolutely the right moment to sit down together'

PROFILES

THE GENOME WARRIOR

Craig Venter has grabbed the lead in the quest for biologies Holy Grail. BY RICHARD PRESTON THE NEW YORKER JUNE 12 2000

Craig Venter is an asshole. He's an idiot. He is a thorn in people's sides and an egomaniac," a senior scientist m the Human Genome Project said to me recently. The Human Genome Project is a nonprofit intemational research consortium that since the late nineteeneighties has been working to decipher the complete sequence of nucleotides in human DNA. The human genome is the total amount of DNA that is spooled into a set of twenty-three chromosomes in the nucleus of every typical human cell. It is often referred to as the book of human life, and most scientists agree that deciphering it will be one of the great achievements of our time. The stakes, in money and glory, to say nothing of the future of medicine, are huge. In the United States, most of the funds for the Human Genome Project come from the National Institutes of Health, and it is often referred to, in a kind of shorthand, as the "public project," to distinguish it from for-profit enterprises like the Celera Genomics Group, of which Craig Venter is the president and chief scientific officer. "In my perception," said the scientist who was giving me the dour view of Venter, "Craig has a personal vendetta against the National Institutes of Health. I look at Craig as being an extremely shallow person who is only interested in Craig Venter and in making money. Only God knows what those people at Celera are doing." What Venter and his colleagues are doing is preparing to announce, in the next few days or weeks, that they have placed in the proper order something like mnety-five per cent of the readable letters in the human genetic code. They refer to this muestone as First Assembly. They have already started selling information about the genome to subscribers.The Human Genome Project is also on the verge of announcing a milestone: what it calls a "working draft" of the genome, which is more than ninety-per-cent complete and is available to anyone, free of charge, on a Web site called GenBankIt contains a large number of fragments that have not yet been placed in order, but scientists in the public project are scrainbeng to get a more complete assembly. Both images of the human genome-Celera's and the public project are becoming clearer and clearer. The human book of life is opening, and we hold it in our hands. A human DNA molecule is about a metre long and a twenty-millionth of a metre wide-the width of twenty hydrogen atoms. It is shaped like a twisted ladder, and each rung of the ladder is made up of four nucleotides-adenine, thymine, cytosine, and guanine. The DNA code is expressed in combinations of the letters A, T, C, and G, the first letters of the names of the nucleotides. The human genome contains at least 3.2 billion letters of genetic code, about the number of letters in two thousand copies of "Moby Dick-" Perhaps three per cent of the human code consists of genes, which hold recipes for making proteins. Human genes are stretches of between a thousand and fifteen hundred letters of code, often broken into pieces and separated by long passages of DNA that don't code for protein. It is believed that there are somewhere between thirty thousand and possibly more than a hundred thousand genes in the human genome (there's great puzzlement about the number). Much of the rest of the genome consists of blocks of seemingly meaningless letters, gobbledygook. These sections are referred to as junk DNA, although it may be that we just don't understand the fiinction of the apparentjunk. The conventional route for announcing scientific breakthroughs is publication in a scientificjoumal, and both Celera and the public project plan to publish annotated versions of the human genome later this year, perhaps in Science. It is even possible that they will announce a collaboration and publish together. Although right now the two sides look like armies maneuvering for advantage, the leaders of the Human Genome Project have consistently denied that they are involved in some kind of competition. "They're trying to say it's not a race, right?" Craig Venter said to me recently, in a shrugging sort of way. "But if two sailboats are sailing near each other, then by definition it's a race. If one boat w'ms, then the winner says,'We smoked them,' and the loser says,'We weren't racingwe were just cruising."'

I first met Craig Venter on a windy day lin summer nearly a year ago, at Celera's headquarters in Rockville, Maryland, a half-hour drive northwest of Washington, D.C. The company's offices and laboratories occupy a pair of five-story white buildings with mirrored windows, surrounded by beautiful groves of red oaks and tulip-poplar trees. One of the buildings contains rooms packed with row after row of DNA-sequencing machines of a type known as the ABI Prism 3700. The other building holds what is said to be the most powerfid civilian computer array in the world; it is surpassed only, perhaps, by that of the Los Alamos National Laboratory, which is used for simulating nuclear bomb explosions. This second building also contains the Command Center, a room stuffed with control consoles and computer screens. People in the Command Center monitor the flow of DNA inside Celera. The DNA flows through the Prism machines twenty-four hours a day, seven days a week. That day last summer, Venter moved restlessly around his office. There had been a spate of newspaper stories about the race to decode the complete genome, and about the pressure Celera was putting on its competitors. "We're scaring the shit out of everybody, including ourselves," he said to me. Venter is fiftythree years old, and he has an active, cherubic face on which a smile often flickers and plays. He is bald, with a fuzz of short hair at the temples, and his head is usually sunburned. He has bright-blue eyes and a soft voice. He was wearing khaki slacks and a blue shirt, New Balance running shoes, a preppy tie with small turtles on it, and a Rolex watch. Venter's office looks into the trees, and that day leaves were spinning on branches outside the windows, flashing their white undersides and promising rain. Beyond the trees, a chronic traffic jam was occurring on the Rockville Pike. Celera is in an area along a stretch of Interstate 270 known as the Biotechnology Corridor, which is dense with companies specializing in the life sciences. Celera Genomics is a part of the PE. Corporation, which was called PerkinElmer before the company's chief executive, Tony L. White, split the business into two parts: P.E. Biosystems, which makes the Prism machine, and Celera. Venter owns five per cent of Celeds stock, which trades, often violently, on the New York Stock Exchange. In recent months, the stock has been tossed by waves of panic selling and panic buying. Currently, the company is valued at three billion dollars, more or less. At times, Craig Venter's net worth has slopped around by a hundred million dollars a day, like water going back and forth in a bathtub. "Our fundamental business model is hke Bloomberg's," Venter said. "We're selling information about the vast universe of molecular medicine." Venter beEeves, for example, that one day Celera will help analyze the genomes of millions of people as a regular part of its business-this will be done over the Internet, he says-and the company wiu then help design or select drugs tailored to patients'particular needs. Genomics is moving so fast that it is possible to think that in perhaps fifteen years you win be able to walk into a doctor's office and have your own genome interpreted. It could be stored in a smart card. (You would want to keep the card in your wallet, in case you landed in an emergency room.) Doctors would read the smart card, and it would show a patient's total biological-software code. They could see the bugs in the code, the genes that make you vulnerable to certain diseases. Everyone has bugs in his code, and knowing what they are will become a key to diagnosis and treatment. If you became sick, doctors could watch the activity of your genes, using so-called gene chips, which are small pieces of glass containing detectors for every gene. Doctors could track how the body was responding to treatment. All your genes could be observed, operating in an immense symphony. Venter stopped moving briefly, and sat down in front of a screen and tapped a keyboard. A Yahoo! quote came up. "Hey, we're over twenty today," he said. (Celera's stock has since split. Adjusted for today's prices, it was trading at ten dollars a share; last week, it was trading at around seventy dollars a share.) I was standing in front of a large model of Venter's yacht, the Sorcerer, in which he won the 1997 Trans-Adantic Race in an upset victory it was the only major ocean race ttiat Venter had ever entered. "I got the boat for a bargain from the guy who founded Land's End," Venter said. "I hke to buy castoff things on the cheap from ultra-rich people." Venter went into the hallway, and I followed him. Celera was renovating its space, and tiles were hanging from the ceiling. Some had fallen to the floor. Black stains dripped out of airconditioning vents, and sheets of plywood were lying around. Workmen were Sheetrocking walls, ripping up carpet, and installing light fixtures, and a smell of paint and spackle drifted in the air. We took the stairs to the basement and entered a room that held about ffty ABI Prism 3700 machines. Each Prism was the size of a small refrigerator and had cost three hundred thousand dollars. Prisms are the fastest DNA sequencers on earth. At the moment, they were reading the DNA of the fruit fly. This was a pilot project for the human genome. The machines contained lasers. Heat from the lasers seemed to ripple from the machines, even though they were being cooled by a circulation system that drew air through them. The lasers were shining light on tiny tubes through which strands of fruit-fly DNA were moving, and the light was passing through the DNA, and sensors were reading the letters of the code. Each machine had a computer screen on which blocks of numbers and letters were scrolling past. It was fly code. "You're looking at the third-largest DNA-sequencing facility in the world," Venter said. "We also have the secondlargest and the largest." We got into an elevator. The walls of the elevator were dented and bashed. Venter led me into a vast, low-ceilinged room that looked out into the trees. This was the largest DNA-decoding factory on earth. The room contained a hundred and fifty Prisms-forty-five million dollars'worth of the machines and more Prisms were due to be installed any day. Air ducts dangled on straps from the ceiEng, and one wall consisted of gypsum board. Venter moved restlessly through the unfinished space. "You know, this is the most fiituristic manufacturing plant on the planet right now," he said. Outdoors, the rain came, splattering on the windows, and the poplar leaves shivered. We stopped and looked over a sea of machines ' seeing Henry Ford's first assembly plant," he said. "What did you see? People, right? There are three people working in this room. A year ago, this work wotdd have taken one thousand to two thousand scientists. With this technology, we are literally coming out of the dark ages of biology. a civilization, we know far less than one per cent of what will be known about biology, human physiology, and medicine. My view of biology is'We dont know shit."' Celera's business model provokes some interesting questions, and some observers believe the company coidd fail. For instance, it appears to be burning through at least a hundred and fifty million dollars a year. But who win want to buy the information the company is generating, and how much win they pay for it? "There will be an incredible demand for genomic information," Venter assured me. "When the first electric-power companies strung up wires on power poles, there were a lot of skeptics. They said, 'Who's going to buy all that electricity.' We already have more than a hundred million dollars in committed subscription revenues over five years from companies that are buying genomic information from us-Amgen, Novartis, Pharmacia &Upjohn, and others. After we finish the human genome, we'll do the mouse, rice, rat, dog, cow, corn, maybe apple trees, maybe clover. We'll do the chimpanzee."

One day at Celera's headquarters, I was takng with a molecular biologist named Hamilton 0. Smith, who won a Nobel Prize in 1978 as the codiscoverer of restriction enzymes, which are tised to cut DNA in specific places. Scientists use the enzymes like scissors, chopping up pieces of DNA so that they can be studied'or recombined with the DNA of other organisms. Without the means to do this, there would be no such thing as genetic engineering. Ham Smith is in his late sixties. He is six feet five inches tall with a shock of stiff white hair and a modest manner. "Have you ever seen human DNA?" he asked me, as he poked around his lab. "No." "It's beautiful sruff A box that held four small plastic tubes, each the size of a pencil stub, sat on a countertop. "These four tubes hold enough human DNA to do the entire human-genome project," Smith said. "There's a couple of drops of Equid in each tube." He held up one of the tubes and turned it over in the light to show me. A droplet of clear liquid moved back and forth. It was the size of a dewdrop. Then he held up a glass vial, and rocked it back and forth, and a crystal-clear, syrupy liquid oozed around in it. He explained that this was DNA he'd extracted from human blood-from white cells. "That's long, unbroken DNA. This liquid looks glassy and clear, but it's snotty. It's like sugar syrup. It really is a sugar syrup, because there are sugars in the backbone of the DNA molecule." Smith picked up a pipet-a handheld device with a hollow plastic needle in it, which is used for moving tiny quantities of Equid from one place to another. His hands are large, but they moved with precision. Holding the pipet, he sucked up a droplet of DNA mixed with a type of purified salt water called buffer. He held the drop in the pipet for a moment, then let it go. The droplet drooled. It reminded me of a spider dropping down a silk thread. "There the DNA goes, it's stringing," he said. "The pure stuff is gorgeous.), The molecules were seding along one another, like spaghetti falling out of a pot, causing the water to string out. "It's absolutely glassy clear, without color," he ' "Sometimes it pulls back into the said. tube and won't come out. I guess that's fike snot, too, and then you have to almost cut it with scissors. mo I e is actually quite stiff. It's hke a plumber's snake. It bends, but only so much, and then it breaks. It's brittle. You can break it iust by stirring it." The samples of DNA that Celera is using are kept in a freezer near SmitHs office. When he wants to get some human DNA, he removes a vial of frozen white blood cells or sperm from the freezer. The vials have coded-labels. He thaws the sample of cells or sperm, then mixes the material with salt water, along with a little bit of detergent. A typicall human cell looks like a fried egg, and the nucleus of the cell resembles the yolk. The detergent pops the eggs and the yolks, and strands of DNA spill out in the salt water. The debris falls to the bottom, leaving tangles of DNA suspended in the Equid. One of Smith's research associates, a woman named Cindi Pfannkoch, showed me what shattered DNA was like. Using a pipette she drew a tiny amount of Equid from a tube and let a drop go on a sheet of wax, where it beaded up like a tiny jewel, the size of the dot over this "i." An ant could have drunk it in fidl. "There are two hundred million fragments of human DNA in this drop," she said. "We call that a DNA library." She opened a plastic bottle, revealing a white fluff. "Here's some dried DNA." She took up a pair of tweezers and dragged out some of the fluff It was a wad of dried DNA from the thymus gland of a calf, the wad was about the size of a cotton ball, and it contained several million miles of DNA. "In theory," Ham Smith said, "you could rebuild the entire calf from any bit of that fluff." I placed some of the DNA on the ends of my fingers and rubbed them together. The stuff was sticky. It began to dissolve on my skin. "It's melting-like cotton candy," I said. "Sure. That's the sugar in DNA," Smith said. "Would it taste sweet?" "No. DNA is an acid, and it's got salts in it. Actually, I've never tasted it." Later, I got some dried calf DNA. I placed a bit of the fluff on my tongue. It melted into a gluey ooze that stuck to the roof of my mouth in a blob. The blob felt slippery on my tongue, and the taste of pure DNA appeared. It had a soft taste, unsweet, rather bland, @th a touch of acid and a hint of salt. Perhaps like the earth's primordial sea. It faded away.

DNA from six donors who contributed their blood or semen was used for Celera's human-genome project. The donors included both men and women, and a variety of ethnic groups. just one person, a man, supplied the DNA for First Assembly. Ordy Craig Venter and one other person at the company are said to know who the donors are. "I don't know who they are, but I wouldn't be surprised if one of them is Craig," Ham Smith remarked.

Craig Venter grew up in a workingclass neighborhood on the east side of Millbrae, on the San Francisco peninsula. His fainily's house was near the raUroad tracks. One of his favorite clifldhood activities, he says, was to play cEcken on the tracks. In high school, he excelled in science and shop. He built two speed boats, and spent a lot of time surfing Half Moon Bay. He attended two major colleges in a desldtory way but mostly he surfed, until he enlisted in the Navy. He had long blond hair and a crisp body then. He was a medical corpsman in Vietnam, and twice he was sentenced to the brig for disobeying orders. Venter has a history of confrontation with government authorifies. He told me that as an enlisted man in San Diego he was court-martialled for refusing a direct order given by an officer. "She happened to be a woman I was dating," Venter said. "We had a spat, and she ordered me to cut my hair. I refused." A friend of his, Ron Nadel, who was a doctor in Vietnam, recalls that one of Venter's blowups with authority involved "telling a superior officer to do something that was anatomically impossible." Venter worked for a year in the intensive-care ward at Da Nang hospital, where, he calculates, more than a thousand Vietnamese and American soldiers died during his shifts, many of them when the 1968 Tet offensive was going on. When he returned to the United States, Venter finished college and then earned a Ph.D. in physiology and pharmacology from the University of Califonia at San Diego. Venter is married to a molecular biologist, Claire Fraser, who is the president of The Institute for Genomic Research (TlGR, pronounced "Tiger"), in Rockville, a non-profit institute that he and Fraser helped establish in 1992. In 1998, he endowed TIGR half of his original stake in Celera -five per cent of the company. The gift is currently worth about a hundred and fifty milllion dollars, and it will be used to analyze the genomes of microbes that cause malaria and cholera and other diseases. A few years ago, Venter developed a hole in his intestine, due to diverticulitis. He collapsed after giving a speech, and nearly died. He is fine now, but he blames stress caused by his enemies for his burst intestine. Venter has enemies of the first water. They are brilliant, famous, articulate, and regularly angry. At times, Venter seems to thrive on his enemies' indignation with an indifferent grace, like a surfer shooting a tublular wave, letting himself be propelled through their cresting wrath. At other times, he seems baffled, and says he [email protected] understand why they don't like him.

One of Venter's most venerable enemies is James Watson, who, with Francis Crick and Maurice Wilkins, won the Nobel Prize in Medicine in 1962 for discovering the shape of the DNA molecule-what they called the double helix. Watson helped found the Human Genome Project, and he was the first head of the N.I.H. genome program. I visited him in his office at the Cold Spring Harbor Laboratory, on Long Island. The office is panelled in blond oak and has a magnificent eastward view across Cold Spring Harbor. Watson is now in his seventies. He has a narrow face, lopsided teeth, a frizz of white hair, sharp, restless eyes, a squint, and a dreamy way of speaking in sentences that trail off. He put his hands on his head and squinted at me. "In 1953, with our first paper on DNA, we never saw the possibility. . . " he said. He looked away, up at the walls. "No chemist ever thought we could read the molecule." But a number of biologists began to think that reading the human genome might just be possible, and by the midnineteen-eighties Watson had become convinced that the decryption of the genome was an important goal and should be pursued, even if it cost billions and took decades. Watson appeared before Congress in May of 1987 and asked for an initial annual budget of thirty million dollars for the project. The original plan was to sequence the human genome by 2005, at a projected cost of about three billion dollars. The principal work of the project is now carried out by five major DNAsequencing centers, as well as by a number of smaller centers around the worldall academic, nonprofit labs. The big centers include one at Baylor University in Texas, one at Washington University in St. Louis, the Whitehead Institute at M.I.T, the Joint Genome Institute of the Department of Energy, and the Sanger Centre, near Cambridge, England. The Welicome Trust of Great Britain-the largest nonprofit medicalresearch foundation in the world-is fiinding the Sanger work, which is to sequence a third of the human genome. One of the founding principles of the Human Genome Project was the immediate release of all the human code that was found, making it available free of charge and without any restrictions on who could use it or what anyone could do with it. In 1984, Craig Venter had begun working at the N.I.H., where he eventually developed an unorthodox strategy for decodinly bits of aenes. At the time, other scientists were painstakingly reading the complete sequence of each gene they studied. This process seemed frustratingly slow to Venter. He began isolating what are called expressed sequence tags, or E.S.Ts, which are fragments of DNA at the ends of genes. When the E.S.Ts were isolated, they could be used to identify genes in a rough way. With the help of a few sequencing machines, Venter identified bits of thousands of human genes. This was a source of unease at the N.I.H., because it was a kind of skimming rather than a complete reading of genes. Venter published his method in 1991 in an article in Science, along with partial sequences from about three hundred and fifty human genes. The method was not received well by many genomic scientists. It was fast, easy, and powerful, but it didr;t look elegant, and some scientists seemed threatened by it. Venter claims that two of his colleagues, who are now heads of public genome centers, asked him not to publish his method or move forward with it for fear they would lose their funding for genome sequencing. The N.I.H. decided to apply for patents on the gene fragments that Venter had identified. James Watson blew his stack over the idea of anyone trying to patent bits of genes, and he got into a hostile situation with the director of the N.I.H., Bernadine Healy, who defended the patenting effort. In July of 1991, during a meeting in Washington called by Senator Pete Domeriici, of New Mexico, to review the genome program, Watson dissed Venter's methods. "It isn't science he said , adding that the machines could be run by monkeys." It was a strange moment. The Senate hearing room was almost empty - few politicians were interested in genes then. But Craig Venter was sitting in the room. "Jim Watson was clearly referring to Craig as a monkey in front of a U.S. senator," another scientist who was there said to me. "He portrayed Craig as the village idiot of genomics." Venter seemed to almost thrash in his chair, stung by Watson's words. "Watson was the ideal father figure of genomics," Venter says. "And he was attacking me in the Senate, when I was relatively young and new in the field." Today, James Watson insists that he wasn't comparing Craig Venter to a monkey. "It's the patenting of genes I was objecting to. That's why I used the word 'monkey'! I hate it!" he said to me. The patent office turned down the N.I.H.'s application, but a few years later, two genomics companies, Incyte and Human Genome Sciences, adopted the E.S.T method for finding genes, and it became the foundation of their businesses- currently worth, combined, about seven billion dollars on the stock market. Incyte and Human Genome Sciences are Celera's main business competitors. Samuel Broder, the chief medical officer at Celera, who is a former director of the National Cancer Institute, said to me, heatedly, "None of the people who severely and acrimoniously criticized Craig for his E.S.T method ever said they were personally sorry. They ostracized Craig and then went on to use his method with never an acknowledgment." James Watson now says, "The E. S.T method has proved immensely useful, and it should have been encouraged."

Venter was increasingly unhappy at the N.I.H. He had received a tenmillion-dollar grant to sequence human DNA, and he asked for permission to use some of the money to do E.S.T sequencing, but his request was denied by the genome project. Venter returned the grant money with what he says was a scathing letter to Watson. In addition, Claire Fraser had been denied tenure at the N.I.H. Her review committee (which was composed entirely of middle-aged men) explained to her that it could not evaluate her work independently of her husband's. At the time, Fraser and Venter had separate labs and separate research programs. Fraser considered suing the N.I.H. for sex discrimination. Watson was forced to resign as head of the genome project in April of 1992, in part because of the dispute over patenting Craig Venter's work That summer, Venter was approached by a venture capitalist named Wallace Steinberg, who wanted to set up a company that would use Venter's E.S.T method to discover genes, create new drugs, and make money. "I didn't want to run a company, I wanted to keep doing basic research," Venter says. But Steinberg offered Venter a research budget of seventy million dollars over ten years-a huge amount of money, then, for biotech. Venter, along with Claire Fraser and a number of colleagues, left the N.I.H. and founded TIGR, which is a nonprofit organization. At the same time, Steinberg established a for-profit company, Human Genome Sciences, to exploit and commercialize the work of TIGR, which was required to license its discoveries exclusively to its sister company. Thus Venter got millions of dollars for research, but he had to hand his discoveries over to Human Genome Sciences for commercial development. Venter had one foot in the world of pure science and one foot in a bucket of money. By 1994, the Human Genome Project was mapping the genomes of model organsms, wmch included the fruit fly, the roundworm, yeast, and E. coli (the organism that lives in the human gut), but no genome of any organism had been completed, except virus genomes, which are relatively small. Venter and Hamilton 0. Smith (who was then at the Johns Hopkins School of Medicine) proposed speeding things up by using a technique known as whole-genome shotgun sequencing. In shotgunning, the genome is broken into small, random, overlapping pieces, and each piece is sequenced, or read. Then the jumble of pieces is reassembled in a computer that compares each piece to every other piece and matches the overlaps, thus assembling the whole genome. Venter and Smith applied for a grant from the N.I.H. to shotgun-sequence the genome of a disease-causing bacten'um called H. influenzae, or H. flu for short. It causes fatal meningitis in children. They proposed to do it in just a year. H. flu has 1.8 million letters of code, which seemed massive then (though the human code is two thousand times as long). The review panel at the N.I.H. gave Venter's proposal a low score, essentially rejecting it. According to Venter, the panel claimed that an attempt to shotgun-sequence a whole microbe was excessively risky and perhaps impossible. He appealed. The appeals process dragged on, and he went about shotgunning H. flu anyway. Venter and the TIGR team had nearly finished sequencing the H. flu genome when, in early 1995, a letter arrived at TIGR saying that the appeals committee had denied the grant on the ground that the expen'ment wasn't feasible. Venter published the H. flu genome a few months later in Science. Whole-genome shotgunning had worked. This was the first completed genome of a free-living organism. It seems quite possible that Venter's grant was denied because of politics. The review panel seems to have hated the idea of giving N.I.H. money to TIGR to make discoveries that wotdd be turned over to a corporation, Human Genome Sciences. It turned down the grant, in spite of the fact that "all the smart people knew the method was straightforward and woldd work," Eric Lander, the head of the genome center at M.I.T and one of the leaders of the public project, said to me. Around this time, Wallace Steinberg died of a heart attack, and his death provided a catalyst for a split between TIGR and Human Genome Sciences, which was run by a former AIDS researcher, William Haseltine. Venter and Haseltine were widely known to dislike each other. Venter sold his stock in Human Genome Sciences because of the rift between them, and after Steinberg died the relationship between the two organizations was formally ended.

Late in 1997, TIGR was doing some DNA sequencing for the Human Genome Project, and Venter began going to some of the project's meetings. That was when he started calling the heads of the public project's DNA-sequencing centers the Liars' Club, claiming that their predictions about when they wotad finish a task and how much it would cost were false. This did not win Venter many friends. But he seemed to have a point. Francis Collins, a distingushed medical geneticist from the University of Michigan, had become the head of the N.I.H. genome program shortly after James Watson resigned in 1992. In early January, 1998, an internal budget projection from Collins's office somehow found its way to Watson (he seems to find out everything that's happening in molecular biology). This budget projection-it is not clear whether it was formal or was just an unofficial projection-was a document about eight pages long. It contained a graph marked "Confidential" indicating that Collins planned to spend only sixty million dollars per year on direct human-DNA sequencinLy throulrh 2005. It also predicted that by that year--when the human genome was supposed to be completedonly 1.6 billion to 1.9 bilhon letters of human code would be sequenced; that is, slightly more than half of the human genome. This upset Watson, and he decided to discuss it with Eric Lander. On January 17th, Watson travelled to Rocketeller University, on the East Side of Manhattan, where Lander was giving the prestigious Harvey Lecture.ne two men met after the lecture at the faculty club at Rockefeller. They were dressed in black tie and were somewhat inebriated. Traditionally among medical people, the Harvey Lecture is given and listened to under the influence. The Rockefeller faculty club overlooks a lawn and sycamore trees and the traffic of York Avenue. Watson and Lander sat down with cognacs at a small table in a dim corner of the room, on the far side of a pool table, where they could talk without being overheard. Also present and drinking cognac was a biologist named Norton Zinder, who is one of Watson's best friends. Zinder, Eke Watson, is a founder of the Human Genome Project. One of the older men brought up the confidential budget document with Lander, and both of them began to press him about it. They felt that it provided evidence that Collins did not intend to spend more than sixty million dollars a year on human-DNA sequencing-nowhere near enough to get the job done, they felt. Watson evidently felt that Lander had influence with Francis Collins, and he urged him to try to persuade Collins to spend more on direct sequencing of human DNA, and to twist Congress's arm for more money. Norton Zinder was somewhat impaired with cocktails. "This thing is potchkeeing along, going nowhere!" he said, hammering the little table and waving his arms as he spoke. For him, the issue was simple: he had had a quadruple coronary bypass, and he had been receiving treatments for cancer, and now he was afraid he would not live to see the deciphering of the human genome. This was intolerable. The human genome had begun to seem like a vision of Canaan to Norton Zinder, and he thought he wouldn't make it there. Eric Lander did not view things the way the older biologists did. In his opinion, the problem was organizational. The Human Genome Project was "too bloody complicated, with too many groups." He felt the real problem was a lack of focus. He wanted the project to create a small, elite group that would do the major sequencing of human DNA-shock cavalry that would lead a charge into the human genome. Implicitly, he thought its leader should be Eric Lander. The three men downed their cognacs with a sense of frustration. "I had essentially given up seeing the human genome in my lifetime," Zinder says.

At about the same moment that Watson and his friends were lamentng the slowness of the public project, the Perkin-Elmer Corporation, which was a manufacturer of lab instruments, was secretly takng about a corporate reorganization. It controlled more than ninety per cent of the market for DNAsequencing equipment, and it was developing the ABI Prism 3700. The Prism was then only a prototype sitting in pieces in a laboratory in Foster City, California, but already it looked as if it were going to be at least ten times faster than any other DNA-sequencing machine. Perkin-Elmer executives began to wonder just what it could do. One day Michael HunkapiUar, who was then the head of the company's instrument division, got out a pocket calculator and estimated that several hundred Prisms could whip through a molecule of human DNA in a few weeks, although only in a rough way. To fill in the gapsplaces where the DNA code came out garbled or wasn't read properly by the machine it would be necessary to sequence the molecule again and again. This is known as repeat sequencing, or manyfold coverage, and might take a few years. Hunkapinar persuaded the chief executive of Perkin-Elmer Tony Wate, to restructure the business and create a genomics company. In December, 1997, executives from Perkin-Elmer began telephoning Venter to see if he'd be interested in running the new company. He blew them off at first, but in early February, 1998, he went to California with a colleague, Mark Adams, to look at the prototype Prism. When they saw it, they immediately understood its significance. Before the end of that day, Venter, Adams, and Hunkapillar had laid out a plan for decoding the human genome. A month later, Norton Zinder, Watson's friend, flew to California to see the machine. "It was just a piece of equipment sitting on a table, but I said,'That's it! We've got the genome!"' he recalled. Zinder joined Celera as a member of its board of advisers, and received stock in the company, which has considerably enriched him. ("The chemists have been cleaning up," he said to me. "Now biologists have their hands on the money, too.") Zinder and Watson have maintained their friendship but have agreed not to speak about Celera with each other. They evidently fear that one or both of them colad have a stroke arguing about Craig Venter.

A t eleven o'clock in the morning on May 8, 1998, Craig Venter and Mike Hunkapillar walked into the office of Harold Varmus, who was then the director of the N.I.H., and announced the pending formation of a corporation, led by Venter, that was going to decode the human genome. (Celera did not yet have a name.) They proposed to Vannus that the company and the public project collaborate, sharing their data and-this point is enormously important to scientists-sharing the publication of the human genome, which meant sharing the credit and the glory for having done the work, including the unspoken possibility of a Nobel Prize. Varmus strongly suspected that this [email protected] a sincere offer, and he told them that he needed time, [email protected] to check with Francis Collins. Later that same day, Venter and Hunkapinar drove to Dulles Airport, where they met Collins at the United Airlines Red Carpet Club, and again offered collaboration. Venter recalls that Collins seemed upset. Collins recalls that he merely asked Venter for time to consider the offer. Time was one thing Venter was not prepared to give. Venter had alerted the New York Times to the story about the creation of the new company, and just an hour or so after the meeting with Collins he called the Times and told the paper it should run it. In the story, Venter announced that he would sequence the human genome by 2001-four years ahead of the public project-and he would do it, he claimed, for between a hundred and ffty and two hundred million dollars-less than a tenth of the projected cost of the public project. The Times reporter, Nicholas Wade, implied that the Human Genome Project might not meet its goals and might be superfluous. Four days later, on May 12th, Venter and Hunkapillar went to the Cold Spring Harbor Laboratory, where a meeting of the heads of the Human Genome Project was taking place. Venter got up and told them, in effect, that they could stop working, since he was going to sequence the human genome tout de suite. Later that week, sitting beside Varmus and Collins at a press conference, Venter looked out at a room filu of reporters and suggested that biology and society would be better off if the Human Genome Project shifted gears and moved forward to do the genome of the ... mouse. It was a fart in church of magnitude nine. "The mouse is essential for interpreting the human genome," Venter tried to explain, but that didn't help. In the words of one head of a sequencing center who was at the Cold Spring Harbor meeting, "Craig has a certain lack of social skills. He goes into that meeting thinking everyone is going to thank him for doing the human genome himself. The thing blew up into a huge explosion." The head of another center recalled, "Craig came up to me afterward, and he said,'Ha, ha, I'm going to do the human genome. You should go do the 'I s ' to him,'You bastard. You mouse. aid bastard,'and I almost slugged him." They felt that Venter was trying to stake out the human genome for himself as a financial asset while at the same time stealing the scientific credit. They felt that he was belittling their work. Venter said that he would make the genome available to the public but would charge customers who wanted to see and work with Cetera's analyzed data. James Watson was fiirious. He did not like the idea of having to pay money to Cra',g Venter for anything. Watson did not attend Venter's presentation, but he appeared in the lobby afterward, where, he repeatedly sm'd to people, "He's Hitler. This should not be Munich." To Francis Collins he said, "Are yougoing to be Churchill or Chamberlain?" Venter left the meeting soon after-ward, and he and Watson have exchanged only chilly greetings since. The British leaders of the public project-John Sulston, the director of the Sanger Centre, and Michael Morgan, of the Wellcome Trust-reacted swiffly to Venter's announcement. They were in England, but they flew to the United States, and the next day arrived at Cold Spring Harbor, where they found things in disarray, if not in fibrillation, with scientists wondering if the Human Genome Project was about to die. To a standing ovation, Michael Morgan got up and read a Churchilhan statement declaring that the Wellcome Trust wotad nearly double its funding for the public project, and would decode a fidl third of the human genome, and wotad challenge any "opportunistic" patents of the genome. "We were reacting, in part, to Craig's suggestion that we just close up shop and go home," Morgan says now. Venter also announced that Celera would use the whole-genome shotgun method. The pubec project was using a more conventional method. John Sulston and Robert Waterston, the head of the sequencing center at Washington University, published a letter in Science asserting that Venter's method would be "woefilUy inadequate." Francis ColEns was quoted in US,4 Today as saying that Celera was going to produce "tfle Cliffs Notes or the Mad Magazine version" of the human genome. Collins says now that his words were taken out of context, and he regrets the quote.

The company forged from Perkin-Elmer amid the turmoil was the P.E. Corporation, which holds the RE. Blosystems Group, the unit that makes the Prism machines, and Celera Genomics. Michael Hunkapillar, who is now the president of RE. Biosystems, believed that he could sell a lot of machines to everyone, including the Human Genome Project. There was a fat profit margin in the chemicals the machines use. The chemicals cost far more than the machine over the machine's lifetime. This was the razor-blade pn'nciple: if you put razors in people's hands, you win make money selling blades. In August, Incyte Pharmaceuticals announced that it was starting a humangenome project of its own. In September, James Watson quietly went to some key members of Congress and persuaded them to spend more money on the public project. At the same time, the leaders of the project announced a radical new game plan: they would produce a "working draft" of the human genome by 2001 a year ahead of when Venter said he'd be done a finished, complete version by 2003. An epic race had begun. A couple of months ago, Michael Morgan, of the WeUcome Trust, was takng to me about Venter and what had happened with the creation of Celera. "From the first press release, Craig saw the pubec program as something he wanted to denigrate," Morgan said. "This was our first sign that Celera was setting out to undermine the international effort. What is it that motivates Craig? I think he's motivated by the same things that drive other scientistspersonal ego, a degree of altruism, a desire to push human knowledge forward-but there must be something else that drives the guy. I think Craig has a huge chip on his shoulder that makes him want to be loved. I actually think Craig is desperate to win a Nobel Prize. He also wants to be very, very rich. There is a fiindamental incompatibility there." One day, I ran into a young player in the Human Genome Project. He believed in the worth and importance of the project, and said that he had turned down a job offer from Celera. He didr;t have any illusions about human nature. He said, "Here's why everyone is so pissed at Craig. The whole project started when James Watson persuaded Congress to give him money for the human genome, and he turned around and gave it to his friends-they're the heads of centers today. It grew into a lot of money, and then the question was, Who was going to get the Nobel Prize? In the United States, there were seventeen centers in the project, and there was no quality control. It didn't matter how bad your data was, you just had to produce it, and people weren't being held accountable for the quality of their product. Then Celera appeared. Because of Celera, the N.I.H. was sudderdy forced to consolidate its funding. The N.I.H. and Francis Collins began to dump more than eighty per cent of the money into just three centers-Baylor, Washington University, and M.I.T they jacked everybody else. They had to do it, because they had to race Celera, and they couldn't control too many players. So all but three centers were cut drastically, and some of the labs closed down. Celera was not iust threatening their funding but threatening their very lives and everything they had spent years building. It's kind of sad. Now those people hang around meetings, and the leaders treat them like'lf you're really nice, we'll give you a little piece of the mouse.' That's the reason so many of them are so angry at Celera. lt's easier for them to go after Craig than to go after Francis Collins and the N.I.H."

Celera's headquarters in Rockville, ik was shown how human DNA was shotgunned into small pieces when it was sprayed through a hospital nebulizer that cost a dollar-fifty. The DNA fragments were then introduced into E. coli bacteria, and grown in glass dishes. The bacten'a formed brown spots-cloned on the dishes. Each spot had a different fragment of human DNA growing in it. The dishes were carried to a room where three robots sat in glass chambers the size of small bedrooms. Each robot had an arm that moved back and forth rapidly over a dish. Little needles on the arms kept stabbing down and taking up the brown spots. Craig Venter stood watching the robots move. The room smelled faintly like the contents of a human intestine. "This used to be done by hand. We've been picking fifty-five thousand clones a day," he said. (Later, Celera got that rate up to a hundred and twenty thousand clones a day.) AU the DNA fragments would eventually wind up in the Prism sequencing machines, and what would be left, at the end, was a collection of up to twenty-two million random fragments of sequenced human DNA. Then the river of shattered DNA would come to the computer, and to a computer scientist named Eugene Myers, who with his team devised the First Assembly. Gene Myers has dark hair and a chiselled, handsome face. He wears glasses and a green half-carat emerald in his left ear and brown Doc Martens shoes. He also has a ruby and a sapphire that he will wear in his ear, instead of the emerald, depending on his mood. He is sensitive to cold. On the hottest days of summer, Myers wears a yellow Patagonia fibrepile jacket, and he keeps a scarf wrapped around his neck. "My blood's thin," he explained to me. He says the scarf is a reference to the DNA of whatever organism he happens to be working on. When I first met Myers, in the hot summer of 1999, he was keeping himself warm in his fi-uit-fly scarf. It had a black-and-white zigzag pattern. This spring, Myers started wearing his human scarf, which has a green chenille weave of changing stripes. He intended his scarf to make a statement about the warfare between Celera and the public project. "I picked green for my human scarf because I've heard that green is a positive, healing color," he said. "I really want all this bickering to go away." His office is a cubicle in a sea of cubicles, most of [email protected] are stocked with Nerf guns, Stomp Rockets, and plastic Viking helmets. Occasionally, Myers puts the "Ride of the [email protected]" on a boom box, and in a loud voice he declares war. Nerf battles sweep through Celera whenever the tension rises. Myers fields a compound double-action Nerf Lock-N-Load Blaster equipped with a Hyper*Sight. "Last week we slaughtered the chromosome team," he said to me. Myers used to be a professor of computer science at the University of Arizona in Tucson. He specializes in combinatorial algorithms. This involves the arrangements and patterns of objects. One day in 1995, he got a telephone call from a geneticist namedjames Weber, at the Marshfield Medical Research Foundation in Wisconsin. Weber said he felt that whole-genome shotgunning woiad work for organisms that have very long DNA molecules, such as humans. He wondered if Myers could help him with the math. Jim Weber submitted a proposal to the N.I.H. for a grant-twelve million dollars-to support a pilot study of the shotgun approach on the human genome. This might speed up the project dramatically, he suggested. Weber was invited to speak to the annual meeting of the heads of the project, held in Bermuda. Weber was nervous about it, and wanted Gene Myers to go with him to help explain the math. "Jim asked them to invite me, but they dicht," Myers says. So on February 26, 1996, Jim Weber went alone to the meeting in Bermuda and tried to make a case for shotgunning the human genome. He found himself facing a U-shaped table with about forty people at it. "They trounced Jim," Myers said. "They said it wouldn't work. They'said it would be full of holes. A Swiss-cheese genome that's the term we've often heard. The grant proposal was soundly rejected." Jim Weber says that the Swisscheese analogy was not far off, but that "it would have been much better to get most of the human genome quickly, even with holes in it, so that people could start using the information to understand diseases and begin to find cures for them. It would have been better if the N.I.H. had funded a pilot study. Instead, Gene and his team went out and did it. That is a huge accomplishment." Craig Venter was hanging around while I was talking with Myers. He came up to us and said, "They not only shot Gene down-they ridiculed him. They said he was a kook. We're going to prove that Gene was right, and we're going to prove that there's something fundamentally wrong with the system."

In September 9, 1999, Venter announced that Celera had completed the sequencing of the fruit fly's DNA, and had begun to run human DNA through its sequencing machines-there were now three hundred of them crammed into Building One in Rockville. The Command Center was up and running, and from then on Celera operated in high-speed mode. One day that fall, I talked with the company's informafion expert, a stocky man named Marshall Peterson. He took me to the computer room, in Building Two. To get into the room, Peterson punched in a security code and then placed his hand on a sensor, which read the unique pattern of his palm. There was a clack of bolts sliding back, and we pushed through the door. A chill of cold air washed over us, and we entered a room rifled with racks of computers that were wired together. "What you're looking at in this room is roughly the equivalent of America Online's network of servers," Peterson said. "We have fifty-five miles of fibre-optic cables running through this building." Workmen standing on ladders were installing many more cables in the ceiling. "The disk storage in this room is five times the size of the Library of Congress. We're getting more storage all the time. We need it." He took me to the Command Center, where a couple of people were hanging around consoles. Some of the consoles had not had equipment installed in them yet. A big screen on the wall showed CNN Headline News. "I've got a full-time hacker working for me to prevent security breaches," Peterson said. "We're getting feelers over the Internet all the time-people trying to break into our system." Celera would be dealing with potentially valuable information about the genes of all kinds of organisms. Peterson thought that some of what he called feelers-subtle hacks and unfriendly probes-had been emanating from Celera's competitors. He said he could never prove it, though. Lately, the probes had been coming from computers in Japan. He thought it was American hackers co-opting the japanese machines over the Internet. By October 20th, forty days after Celera started running human DNA

through its machines, the company announced that it had sequenced 1.2 billion letters of human code. The letters came in small chunks from all over the genome. Six days later, Venter announced that Celera had filed provisional patent appecations for six thousand five hundred human genes. The applications were for placeholder patents. The company hoped to figure out later which of the genes would be worth patenting in earnest. A gene patent gives its holder the right to make commercial products and drugs derived from the gene for a period of seventeen years. Pharmaceutical companies argue that patents are necessary, because without them businesses would never invest the hundreds of mdlions of dollars that are needed to develop a new drug and get it through the licensing process of the Food and Drug Administration. ("If you have a disease, you'd better hope someone patents the gene for it," Venter said to me.) On the other hand, parcelling out genes to various private companies could lead to what Francis Collins refers to as the "Balkanization of the human genome," a paralyzing situation that might limit researchers'access to genes. Venter insists that Celera is an information company and that patenting genes is not its mam goal. He has said that Celera wiu attempt to get patents on not more than about three hundred human genes. There is no question that Celera hopes to nail down some very valuable genes-biflion-doUar genes, perhaps.

Celera's stock had drifted since the summer, but around Halloween, as investors began to realize that the company was cranking out the human genome and filing large numbers of placeholder patents-it jumped up to forty dollars a share. (The prices here are pre-split prices. Adjusted for today's prices, the stock moved up to twenty dollars.) On December 2nd, the Human Genome Project announced that it had deciphered most of the code on chromosome No. 22, the second-shortest chromosome in the human genome. This made the reading of the whole genome seem more imminent, and Celera's stock began a spectacular rise. It shot up that day by nine points, to close at over seventy dollars. Then, after the market's close on Thursday, December 16th, Jeff Fischer, a co-founder of the Web site called The Motley Fool, announced that he was buying shares of Celera for his own portfolio. It is called the Rule Breaker Portfolio, and it has famously delivered wealth-Fischer bought A.O.L. very early, for example. On that Friday morning, a great number of people tried to buy Celera, and they drove the stock up twenty points. It was on its way to the pre-split equivalent of more than five hundred dollars a share. That-past summer, it had been trading at fourteen. I went to visit Celera on Tuesday of the following week, and that morning the company's stock could not open for trading. Everyone wanted to buy it, and nobody wanted to sell it. While the stock was halted-at a hundred and one dollars a share-I wandered around. There was a feeling of paralysis in the air, and I sensed that not much work was getting done that day, except by the machines. Employees were checking the quote on the Internet and wondering what their net worth woLAd be when the stock opened. The lobby now sported fish-eye security cameras. The walls smelled of fresh paint, and the floors had a new purple carpet with a pattern that resembled worms. They were meant to look fike fragments of DNA. I found Hamilton 0. Smith in his lab, puttering around with human DNA in tiny test tubes, but his heart was not in the job. He was tired. He explained that he was renovating an old house that he and his wife had bought. He had stayed up all night ripping carpet out of the basement, because new carpets were due to arrive that morning. He had driven to work in his '83 Mercury Marquis. He owned thousands of shares of Celera. Smith passed a computer, stopped, and brought up a quote. Celera had finally opened for trading. It had gapped up-jumped instantly upward-by thirteen points. It was at a hundred and fourteen. Smith's net worth had gapped up by something on toward a million dollars. "Is there no end to this?" he muttered. Craig Venter came into SmitHs lab and asked him to lunch. In the elevator, Smith said to him, "I can't stand it, Craig. The bubble will break." They sat down beside each other in the cafeteria and ate cassoulet from bowls on trays. "This defies common sense," Smith said. "It's really impossible to put a value on this company." "That's what we've been telling the analysts," Venter said.

Later that day, I ended up in Claire Fraser's office at TIGR headquarters, a complex of semi-Mission-style buudings a couple of miles from Celera's offices and labs. Fraser is a tall, reserved woman with dark hair and brown eyes, and her voice has a faint New England accent. She grew up in Saugus, Massachusetts. In high school, she says, she was considered a science geek. "The only lower citizens were the nerdy guys in the audiovisual club. Of course, now they're probably in Hollywood." Her office has an Oriental rug on the floor and a table surrounded by Chippendale chairs. It was originally Venter's office. ("This is Crams extravagant taste, not mine," she explained.) She wore an expensive-looking suit. Two poodles, Cricket and Marley, slept by a fireplace. "Before genomics, every living organism was a black box," she said. "When you sequence a genome, it's like wakng into a dark room and turning on a light. You see entirely new things everywhere." Fraser placed a sheet of paper on the table. It contained an impossibly complicated diagram that looked like a design for an oil refinery. She explained that it was an analysis of the genome of cholera, a single-caned microbe that causes murderous diarrhea. TIGR scientists had finished sequencing the organism's DNA a few weeks earlier. Much of the picture, she said, was absolutely new to our knowledge of cholera. About a quarter of the genes of every microbe that had been decoded by TIGR were completely new to science, and were not obviously related to any other gene in any other microbe. To the intense surprise and wonder of the scientists, nature was fuming out to be an uncharted sea of unknown genes. The code of life was far richer than anyone had imagined. Fraser's eyes moved quickly over the diagram. "Yes ... wow... There may be important transporters here.... You see these transporters in other bacteria, and ... I don't know ... it looks like there could be potential for designing a new drug that could block them."

The phone rang. Fraser walked across her office, picked up the receiver, and said softly, "Craig? Hello. What? It closed at a hundred and twentyfive?" Pause. "I don't know how much it's worth-you're the one with the calculator." Their net worth had jumped above a hundred and fifty million dollars that day. Fraser drove home, and I followed her in my car. Their house is in the country outside Washington. It sits behind a security gate at the end of a long driveway. Venter arrived in a new Porsche. The car would do zero to sixty in five seconds, he said. In the vaulted front hall of the house there was a large stained-glass window showing branches of a willow tree, and there was a model of H.M.S. Victory in a glass case. A jumble of woodworking machines-a bandsaw, a table saw, a drill press-filled a shop attached to the garage. Venter has worked with wood since high school. In the kitchen, Claire fixed dinner for the poodles, while Craig circled the room, talking. "We created close to two hundred millionaires in the company today. I think most of them had not a clue this would happen when they joined Celera. We have a secretary who became a mileonaire today. She's married to a retired policeman. He went out looking to buy a farm." He popped a Bud Light and swigged it. "This could only happen in America. You've got to love this country." Claire fed the poodles. There were no cooking tools in the kitchen that I could see. The counters were empty. The only food I noticed was a giant sack of dog food, sitting on top of an island counter, and two boxes of cold cereal-Quaker Oatmeal Squares and Total. In the guest bathroom, upstairs, there were no towels, and the walls were empty. The only decorative object in the bathroom was a cheap wicker basket piled with little soaps and shampoos they had picked up in hotels. We went to a restaurant and ate steak. "We're in the Wild West of genomics," Venter said. "Celera is more than a scientific experiment; it's a business experiment. Our stock-market capitalization as of today is three and a half billion dollars. That's more than the projected cost of the Human Genome Project. I guess that's saying something. The combined market value of the Big Three genomics companiesCelera, Human Genome Sciences, and Incyt was about twelve billion dollars at the end of today. This wasn't imaginable six months ago. The Old Guard doesn't have control of genomics anymore." He chewed steak, and looked at his wife. "What the hell are we going to do with all this money? I could play around with boats. . . ." Claire started laughing. "My God, I couldn't live with you." "The money's nice, but it's not the motivation," Venter said to me. "The motivation is sheer curiosity."

In December, 1999, Celera and the Human Genome Project discussed whether it would be possible to collaborate. There was one formal meeting, and there were many points of difference. Meanwhile, Celera's stock seemed to go into escape velocity from the earth. In January, it soared over two hundred dollars a share. Celera filed to offer more shares to the public, and declared a twofor-one stock split. Shortly after the split, on February 25th, the stock hit an all-time high of two hundred and seventy-six dollars a share (more than five hundred and fifty dollars, pre-split). Celera's stock-market value reached fourteen billion dollars, and Venter's worth surpassed seven hundred million dollars. It looked as if Venter could become a billionaire of biotechnology. Then, on March 6th, newspapers carried reports that the discussions between Celera and the public project had collapsed. The main point of disagreement, according to officials at the public project, was that Celera wanted to keep control of intellectual property in the human genome. Celera intended to license its analyzed database to pharmaceutical companies and nonprofit research institutions, for payment. Celera said that it would let anyone use the data, but that any other company would be forbidden from reselling the data. The Human Genome people insisted that the period of restriction on the data could be for no more than a year, and after that the data should be totally pubEc. Celera argued that it didn't want its competitors to resell the information and profit from Celera's work Cetera!s stock began to drop. On March 14th, President Clinton and Prime Minister Blair of Great Britain released a joint statement to the effect that all the genes in the human body "should be made freely available to scientists everywhere." The statement had been drafted with the help of Francis Collins and his staff, and had been in the works for a year. It was vague, but it looked like an Anglo-American smart bomb aimed at Celera, and it scared the dayEghts out of investors in biotechnology stocks, who feared that potentially lucrative patents on genes might be undermined by some new government pohcy. On the day of the Clinton-Blair statement, Celera's stock went into a screaming nosedive. It dropped fiftyseven dollars in a matter of hours, amid trading halts and order imbalances. The other genomic stocks crashed in sympathy with Celera, and this, in turn, dragged down the Nasdaq, which that day suffered the second-largest point loss in its history. Short-seners-people who profit from the decline of a stock-encrusted Celera like locusts. As of writing, the Nasdaq has not recovered. Venter's mother telephoned him after-ward, and said to him, "Craig, you've managed to do overnight what Alan Greenspan has been trying to do for years." "It's not every day you get attacked by the President and the Prime Minister," Venter said to me late that night on the telephone. "I'm expecfing a call from the Pope any day now, asking me to recant the human genome." He sounded wired and exhausted. "I feel a little like Gallileo. They offered to have a barbecue with him, right? Look, I'm not likening myself to Gallileo in terms of genius, but it is clear that the human genome is the science event of our time. I am going to publish the genome, and that's what the threat to the public order is. If Celera was keeping the genome a secret, the way Incyte and Human Genome Sciences are, you wouldn't hear a peep out of the government. Our publishing the genome makes a mockery of the fifteen years and billions of dollars the public project has spent on it." Venter seemed particularly upset with the British part of the pubec project. "In my opinion," he said, "the Wellcome Trust is now trying to justify how, as a private charity, it gave what I think was well over a billion dollars to the Sanger Centre to do just a third of the human geno;ne, largely at the expense of the rest of Brifish medical science. Clinton and Blair took forty billion dollars out of the biotechnology industry today that's how much was lost by investors. It was money that would pay for cures for cancer, and it was taken off the table, afl because some bastards at the Weflcome Trust are trying to cover up their losses." I called Michael Morgan, at the Wellcome Trust, to see what he had to say about this. "In hindsight, it is easy to ascribe to us Machiavellian powers that the Prince would have been proud of," he said dryly. "As for the allegation that I'm a bastard, I can easily disprove it using the technology of the Human Genome Project." The day after the Clinton-Blair statement and the crash in biotech stocks, a White House spokesman made a point of telling reporters that the Administration supported the patenting of genes.

On March 24th, Venter and his colleagues published a substantially complete genome of the fruit fly Drosopbila-in Science. It was also published by Celera on a CD, which Venter had placed on the chairs of thirteen hundred fly researchers at a conference in Pittsburgh. Venter emphasized the fact that the fly genome had been a collaboration with a publicly funded project. In other words, he was suggesting there was no real reason that the Human Genome Project couldn't collaborate with Celera, too. The fly projectknown as the Berkeley Drosophila Genome Project-is headed by a fly geneticist named Gerald Rubin. "One of the things I really like about Craig Venter is that he almost totally lacks tact," Rubin said to me. "If he thinks you are an idiot, he will say so. I find that way of dealing very enjoyable. Craig is like somebody who's using the wrong fork at a fancy dinner. He'll tell you what he thinks of the food, but he won't even think about what fork he's using. It was a great collaboration." John Sulston, the head of the Sanger Centre, told the BBC that he felt Celera planned to "Hoover up all the public data, which we are producing, add some of their own, and sell it as a packaged product." He added, "The emerging truth is absolutely extraordinary. They really do intend to establish a complete monopoly position on the human genome for a period of at least five years," and he said, "It's something of a con job."

"Sulston essentially called us a fraud. It's like he's been bit by a rabid animal," Venter fumed. "It's puzzling. To me, the whole fight defies rational analysis," Hamilton 0. Smith said to me, shortly after his net worth had cratered in Celera's mudshde. "But the pubecly funded labs are angry for reasons I can partly understand. We took it away from them. We took the big prize away from them, when they thought they would be the team that would do the whole human genome and go down in history. Pure and simple, they hate us."

On April 6th, Venter announced that Celera had finished the sequencing phase of the human genome, and was moving on to First Assembly. Celera had produced some eighteen million fragments of the first genome, perhaps Craig Venter's. Soon afterward, on an unseasonably warm day, while the cherry trees were in fiffl blossom, I visited Celera to see how the assembly was going. I found Gene Myers in his cubicle, looking chilled. He was bundled up in his yellow fibrepile jacket and his green human scarf. He and his team had started running chunks of human DNA code through the computers over the weekend. The first run had resulted in a mess something was wrong with the software. They had done some tweaks, and they were running a few more chunks of code. It would take months to assemble the whole thing. 'Assembly is pretty boring," he said, somewhat apologetically. Myers said that Celera would be using all of the Human Genome Project's human DNA code-which was published on the GenBank Web siteand would tear it into fragments and compare them with Celera's DNA code, and then the software that his team had written would try to assemble all the fragments into a whole human genome. At the same time, Celera was coolly telling the public project that its scientists could see Celera's data but only if they came to look at the data on Celera's computer. The collaboration had never come to pass. Minutes later, one of Myers's people, a computer scientist named Knut Reinert, hurried in, and told him that the first assembled human-genome sequence had just come out of the computers. Myers put the "Ride of the Valkyries" on the boom box, and fifteen people tried to crowd into Reinert's cubicle. Myers bent over Reinert's shoulder and said, "We got it! We got the first one! This is the first assembled human sequence we've gotten out of nature!" What appeared on the screen was a mathematical diagram of a stretch of human DNA. It showed arrows going in various directions, connecting dots together. "The picture looks like a Super Bowl debriefing," one Celera programmer remarked. They talked about it for a few minutes, and then everyone drifted back to work. That day, Celera's stock dropped another twenty per cent.

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In early May, another company got into the business of the human genome. DoubleTwist, Inc., announced that it had teamed up with Sun Microsystems to compete with Celera. DoubleTwist and Sun were offering an analyzed database of the human genome to anyone for a fee, using the data from the Human Genome Project, not from Celera. The price was six hundred and fifty thousand dollars for a database that wowd be updated regularly. At the same time, Celera's stock had gone down below a hundred dollars a share. Many investors had recently bought the secondary offering, paying two hundred and twenty-five dollars a share for it. This brought on a slew of class-action lawsuits against Celera, filed by law firms specializing in shareholder suits. There were various claims, sparked by the fact that the secondary investors had lost sixty per cent of their money. These lawsuits wiu probably be consolidated, and Celera will either setde or fight them in court. As for the science, knowledgeable observers believed that, in the end, Celera had actually spent about half a billion dollars to sequence the human genome-three hundred million more than Venter had originally predicted. Was it worth it? I asked many biologists about this, and most of them spoke the way scientists do when they believe that a great door has been opened, and light is shining deep into nature, suggesting the presence of rooms upon rooms that have never been seen before. There was also a clear sense that the door would not have been opened so soon if Craig Venter and Celera had not given it a swift kick. "We can thank Venter in retrospect," James Watson said, leaning back and smiling and squinting at the ceiling. "I was worried he could do it, and that would stop public fiinding of the Human Genome Project. But if an earthquake suddenly raided through Rockville and destroyed Celera's computers, it wouldn't make much difference." He stood up, and offered me the door. Eric Lander, who professes to like Venter, said, "Having the human genome is like having a Landsat map of the earth, compared to a world where the map tapers off into the unknown, and says,'There be dragons.'It's as different a view of human biology as a map of the earth in the fourteen-hundreds was compared to a view from space today." As for the war between Celera and the public project, he said, "At a certain level, it is just boys behaving badly. It happens to be the most important project in science of our time, and it has all the character of a schoolyard brawl." Norton Zinder, Watson's friend, who had feared that he would die before he saw the human genome, said that he felt marvellous. "I made it. Now I've gotta stay alive for four more years, or I won't get all my options in Celera." Zinder, who is a vigorous-seeming older man, was sprawled in a chair in his office overlooking the East River, gesturing with both hands raised. He shifted gears and began to look into the future. "This is the beginning of the beginning," he said. "The human genome alone doesn't ten you crap. This is like Vesalius. Vesalius did the first human anatomy." Vesalius published his work in 1543, an anatomy based on his dissections of cadavers. "Before Vesalius," Zinder went on, "people [email protected] even know they had hearts and lungs. With the human genome, we finally know what's there, but we still have to figure out how it all works. Having the human genome is Eke having a copy of the Talmud but not knowing how to read Aramaic." +